Method of treating or preventing Ras-mediated diseases

Abstract

Disclosed are compounds, for example, a compound of formula I,wherein R, R0, R1-R8, n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition for example, cancer, mediated by the ras gene.

The invention claimed is: 
     
       1. A method of inhibiting growth of a tumor in a human patient, said tumor having been determined to contain a mutant ras gene encoding for expression of a hyperactive Ras, the method comprising administering to said patient a prodrug of formula II, (Z)- or (E)-isomer thereof, or pharmaceutically acceptable salt thereof, wherein said prodrug of formula II is: 
       
         
           
           
               
               
           
         
         wherein: 
         R and R 0  are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; 
         n is 0, 1, or 2; 
         Y and Y′ together is double-bonded oxygen; 
         R 1 , R 3 , and R 4  are hydrogen and R 2  is selected from halogen and alkoxy; 
         R 7  is hydrogen; 
         R 8  is alkyl; 
         R 12  and R 16  are hydrogen; R 13 , R 14 , and R 15  are alkoxy; and 
         X is NR′R″, where R′ is an unsubstituted group selected from phenyl and benzyl; and R″ is hydrogen; 
         wherein R 14  of said prodrug is converted in vivo in said patient to a Ras-inhibitory effective amount of a compound of formula II wherein R 14  is hydroxyl. 
       
     
     
       2. The method of  claim 1 , wherein the prodrug is selected from:
 (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide, 
 (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide, 
 (Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide, and 
 (Z)-N-benzyl-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       3. The method of  claim 2 , wherein the prodrug is:
 (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide. 
 
     
     
       4. The method of  claim 2 , wherein the prodrug is:
 (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide. 
 
     
     
       5. The method of  claim 2 , wherein the prodrug is:
 (Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide. 
 
     
     
       6. The method of  claim 2 , wherein the prodrug is:
 (Z)-N-benzyl-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide.